Methods of surgery underwent a revolution when anesthetics became available that caused the patient to enter a state of reversible loss of sensation and consciousness prior to and during surgical procedures. The anesthetic thereby protects the patient against pain by causing the patient to enter a deep sleep and providing a measure of amnesia concerning events undertaken during sedation. General anesthetics cause profound loss of consciousness with varying hypnotic, analgesic and amnestic potencies (Dundee, J. W., In: Nunn, J. F., et al., eds. General Anesthesia, London: Butterworths, 1989: 115-134). (For the purposes of this disclosure and the following claims, "general anesthesia" is understood as a state of reversible loss of sensation and consciousness. Similarly, "analgesia" is understood as a state of reduced sensibility to pain, which may occur apart from loss of consciousness and loss of the sense of touch. Also similarly, "amnesia" is understood as total or partial loss of memory of events that occurred while under general anesthesia.)
Current methods of general anesthesia involve the administration of an anesthetic gas through a tube placed in the bronchial passage of the patient thereby causing a state of deep sleep. Prior to the introduction of the tube, it is desirable to administer a fast acting sleep inducing agent to minimize discomfort to the patient incurred by the introduction of a tube into the trachea. In fact, the sleeping patient, although unconscious, still responds to pain, and the patient's reaction during introduction of the tube into the trachea can make insertion difficult or impossible causing the procedure to be halted to avoid potentially lethal consequences.
Inducing agents include either barbiturates or steroids which when administered by intravenous injection, cause the patient to rapidly enter a state of deep sleep. Barbiturates are administered in relatively high doses and there is a risk of lethal effects if the dose exceeds the optimal level by a small amount. Although barbiturates are effective in inducing a deep sleep very quickly, patients may take many hours to recover to normal wakefulness. This has the undesirable effect of rendering the patient unable to leave the healthcare facility after a procedure until the effect of the barbiturates disappear even when the actual procedure is relatively short.
An alternative to barbiturates is steroid anesthetics. The potential advantages of steroid anesthetics are lack of toxicity, good overall safety and rapid elimination by liver metabolism providing rapid recovery of the patient from anesthesia. Certain hormonal steroids as well as steroid anesthetics devoid of hormonal activity were recognized to produce anesthesia in rats over 50 years ago (Selye H., et al., Anesthesiology 1943; 4: 38-47). Until today, however, their mode of action on brain function is unknown, as are the factors that cause some steroids to be more effective anesthetics then others (Mok, W. M., et al., J. Neurochem. 1991; 57:1296-1301). One important disadvantage of steroids is their poor solubility in aqueous solutions, a serious drawback in formulating the anesthetic for intravenous administration. Efforts in improving the utility of steroid anesthetics have focused on selecting maximally active steroidal structures that are free of unwanted side effects and formulating these structures in a suitable vehicle for intravenous injection.
The steroid anesthetics and other intravenously administered general anesthetics produce deep sleep, but do not produce analgesia (Dundee, J. W., 1989; Way, W. L., et al., In: Miller, R. D., ed., Anesthesia, New York: Churchill Livingstone, 1986: 799-835; Sutton, J. A., Postgrad. Med. J. (June Suppl.) 1992: 9-13; Mok, W. M., et al., 1991; Hogskilde, S. et al., Anaesthesia 1987, 42:1045-1050). It could be argued on this basis that steroids are not true general anesthetics. The question of why these anesthetics are not analgesic is of fundamental interest.
Steroids are recognized as playing a physiological role in regulating brain function although until this time, the mechanism by which these molecules work is unknown. This has prevented the development of a mechanistic approach to developing improved steroid anesthetics. Indeed, the development of anesthetics has been largely empirical requiring extensive screening of different chemical structures in animal models to determine improved anesthetic effect without detrimental side effects.
Despite the above limitations, steroids have been successfully used as inducing agents prior to general anesthesia. However, their utility could be further improved if in addition to anesthetic properties, the steroid preparations also had analgesic properties. The administration of an inducing agent having analgesic properties would facilitate the insertion of the tube for gaseous administration of a general anesthetic in a patient who would no longer feel pain that causes them to react during the procedure. An additional advantage of an anesthetic with analgesic properties would be the reduction in the dose of anesthetic required to protect the patient against pain. This would have special benefit in short but painful procedures such as correcting a dislocated shoulder where relatively deep protection against pain is required but where the procedure instantly corrects the medical condition thereby potentially enabling the patient to return home at completion of the procedure.
An additional motivation for identifying novel anesthetics results from observed side effects seen in patients using existing anesthetic formulations. For example, Althesin, a composition that initially showed promise as a first rapid acting steroid anesthetic was discovered to cause undesirable clinical side effects. This formulation consists of the steroid, alphaxalone (3-.alpha.-hydroxy-5-.alpha.-pregnane 11.20 dione mixed with a second steroid, alphadolone acetate (21-acetoxyl derivative) dissolved in Cremaphor, a biologically acceptable medium. An example of these undesirable effects include anti-analgesic properties when administered at subanesthetic doses where a transient increase in the appreciation of somatic pain is observed (Corssen, et al., Intravenous anesthesia and analgesia, Philadelphia: Lea and Febiger, 1988). It would be highly desirable to be able to reduce the dose of steroid anesthetic to obtain the required effect so that the probability of adverse side effects from the steroids would be reduced.
For the foregoing reasons, there is a need for a composition for use in preparing animal subjects for surgery that provides the maximum anesthetic effect including the ability to provide analgesia, rapidly at the minimum dose with minimal toxicity and can be safely and easily administered to the animal subject.